Anais da Academia Brasileira de Ciências (2014) 86(1): 451-457

(Annals of the Brazilian Academy of Sciences)

Printed version ISSN 0001-3765 / Online version ISSN 1678-2690
http://dx.doi.org/10.1590/0001-3765201420120036
www.scielo.br/aabc

Patterns of Antimicrobial therapy in acute tonsillitis:

A cross-sectional Hospital-based study from UAE

LISHA J. JOHN1, MEENU CHERIAN2, JAYADEVAN SREEDHARAN3 and TAMBI CHERIAN2

1
Department of Pharmacology, Gulf Medical University, 4184, Ajman, United Arab Emirates
2
Department of ENT, Gulf Medical College Hospital, 4184, Ajman, United Arab Emirates
3
Statistical Support Facility, Centre for Advanced Biomedical Research and Innovation, Gulf Medical University,
4184, Ajman, United Arab Emirates

Manuscript received on December 20, 2012; accepted for publication on October 14, 2013

ABSTRACT
Background: Diseases of the ear, nose and throat (ENT) are associated with significant impairment of
the daily life and a major cause for absenteeism from work. Aim: The study determined antimicrobial
prescription pattern in patients with acute tonsillitis. Materials and Methods: A cross-sectional study was
carried out among all the patients attending the ENT department with acute tonsillitis. Data were retrieved
from the medical records using a proforma. Statistical analysis was carried out using SPSS.19. Results: Total
of 238 patients included (Males 138; females 100). About 96% of total drugs were prescribed by generic
name. Median number of drugs prescribed was four (range 1-7). Eighty eight percent of prescriptions
contained antimicrobials, (78.5%) analgesics and (57.9%) antipyretics. Amoxicillin / Clavulanic acid
(24.8%) and Ceftriaxone (12.2%) were the most commonly prescribed antimicrobials. Parenteral route
was preferred in 41.6%. About 23.7% of the patients on Amoxicillin / Clavulanic acid had received the
drug as intravenous injection. Culture and sensitivity tests were carried out in 106 (44.5%) of the cases.
Antimicrobials were changed / added after the culture and sensitivity test in 25 patients. Conclusion:
Study findings highlighted rational practices in drug prescribing. Therapeutic guidelines based on current
sensitivity pattern optimize the use of antimicrobial agents.
Key words: drug utilization, antimicrobial use, acute tonsillitis, parenteral.

INTRODUCTION This is a major cause for absenteeism from work.

Diseases of the ear, nose and throat (ENT) affect
adults and children, with significant impairment of
the daily life (Grace and Bussmann 2006, WHO
2004). Upper Respiratory Tract Infections (URTIs)
including nasopharyngitis, pharyngitis, tonsillitis and
otitis media constitute a major proportion of the total
episodes of respiratory infections (Jain et al. 2001).
Correspondence to: Lisha Jenny John
E-mail: drlishaj@yahoo.com
The vast majority of acute URTIs are caused by
viruses (Dasaraju and Liu 1996). Inappropriate use
of drugs in the treatment of upper respiratory tract
infections has been previously reported in literature
(Gaash 2008, Brink et al. 2004). This could result
in the development of drug related problems such
as adverse drug reactions and drug resistance, in
addition to increasing the overall cost for health
care (Einarson 2008).

An Acad Bras Cienc (2014) 86 (1)

452 LISHA J. JOHN, MEENU CHERIAN, JAYADEVAN SREEDHARAN and TAMBI CHERIAN
Acute respiratory infections (ARI) accounted
for 20-40% of outpatient and 12-35% of inpatient
attendance in a general hospital (Jain et al. 2001).
In developing countries, 30% of all patients
consultations and 25% of all pediatric admissions
are due to ARI (WHO 2004). Pharyngitis and
tonsillitis account for > 10% of all visits to primary
care clinics and 50% of outpatient antibiotic use
(Linder 2008). In a study from Saudi Arabia that
analyzed the prescriptions for acute respiratory
tract infections, 65.8% of them accounted for upper
respiratory infections (El-Gilany 2000). Naghipour
et al. (2007) reported on the high frequency of
occurrence and transmissibility within the family
cohort in Iran implying the burden of these
infections on the community.
The majority of the antibiotics are prescribed
for ENT infections with a presumed viral etiology.
Acute tonsillitis, where viruses like adenovirus,
Epstein-Barr virus or influenza viruses are implicated,
is treated symptomatically with antipyretics, anti-
inflammatory drugs and mouth gargles, and reassu­
rance to the patients. Several studies have reported
that antimicrobials are prescribed in the management
of URTI due to the drug related problems associated
with inappropriate use (Rehan 2003, Leblebicioglu
et al. 2002, McCaig et al. 2002). The limited role of
antimicrobials in acute tonsillitis of viral etiology has
been published in an overview of Cochrane reviews
by Arroll (2005). In a study published from the
Middle East, antimicrobials were rated as the fourth
most frequently prescribed drugs in primary health-
care facilities (Al Khaja et al. 2008).
In cases of secondary bacterial infection
causing purulent material to accumulate in the
tonsillar crypts, penicillin has been the drug of
choice. Recent results with amoxicillin suggest
that efficacy in acute tonsillitis, is also waning.
Cephalosporins alone or Cephalosporins with
metronidazole where anaerobes are implicated have
the highest bacteriological and clinical efficacy
(Pichichero 2006).
An Acad Bras Cienc (2014) 86 (1)
Antibiotic prescription pattern differs from
country to country, or even from region to region,
which is attributable to various factors such
as the infecting organisms and antimicrobial
susceptibility, physician preference, and costs.
Therefore, it is imperative to evaluate and
monitor the drug utilization patterns periodically,
to enable suitable modifications to be made in
prescribing patterns, in order to increase the
therapeutic benefit and decrease the adverse
effects, and thus optimize the treatment (Srishyla
et al. 1994). Drug utilization studies are designed
to systematically review the drugs prescribed
to the patients. These help provide feedback to
the clinicians, develop protocols that describe
optimal drug use, and promote appropriate drug
use through educating the patients.
Hence, the present prospective study was
aimed at determining the antimicrobial prescription
pattern in adult patients with acute tonsillitis.
MATERIALS AND METHODS
A cross-sectional, hospital-based study was carried
out to evaluate the antimicrobial prescription
pattern in patients with acute tonsillitis. All patients
attending the ENT outpatient department of a tertiary
care hospital, Ajman, UAE from January 2011 to
December 2011 and diagnosed with acute tonsillitis
were included. The approval of institutional Ethics
Committee was obtained before the start of the
study. Incomplete patient records were excluded
from the study. The drug utilization data was
retrieved from the medical records of patients using
a specially designed data collection form. The form
included the following domains: Socio demographic
characteristics (Age, gender, nationality), Clinical
data (Clinical diagnosis, Clinical manifestations,
Examination findings), Laboratory data: (Culture
and sensitivity data: Organism isolated, sensitivity
and resistance pattern), Drug data: (Antimicrobial
agents prescribed, dose and duration of treatment,
 ANTIMICROBIALS IN ACUTE TONSILLITIS 453

change of medication and response to treatment). Among the antimicrobial drug classes, beta-
Statistical analysis was carried out using SPSS19. lactam antimicrobials such as Cephalosporins and
Penicillins were the most frequently prescribed.
RESULTS
Amoxicillin/Clavulanic acid [72 (30.25%)], Ceftria­
Among the total of 238 patients, 138 (57.9%) were xone [40 (16.8%)] and metronidazole [35 (14.7%)]
males and 100 (42.1%) were females. The majority were the most commonly prescribed antimicrobials.
of patients were Indians [49 (20.6%)], Emiratis Of the 264 antimicrobials prescribed, 109 (41.2%)
[35 (14.7%)], and Pakistanis [31 (13%)]. The highest constituted parenteral antibiotics. The commonly
numbers of patients were in the age group 20-29 prescribed parenteral antimicrobials were Ceftriaxone
years and the lowest in the 60-79 years. The gender and Amoxicillin/Clavulanic acid. About 23.7%
and age distribution of patients with acute tonsillitis of the patients were administered Amoxicillin/
is listed in Table I. Clavulanic acid as intravenous injection. The pattern
TABLE I of monotherapy and combination therapy of anti­
Age- and gender-based distribution of microbials in acute tonsillitis is listed in Table III.
patients with acute tonsillitis. The most commonly used fixed drug combination
Variables Group No. % was Amoxicillin/Clavulanic acid [72 (30.25%)].
Male 138 58 Culture and sensitivity test of the throat swab
Gender
Female 100 42 was carried out in 106 (44.5%) of the cases. Of the
1-9 49 20.6
106 throat swabs, bacterial species were isolated in
10-19 17 7.1
20-29 93 39.1 100 cases (94.3%). Alpha hemolytic streptococci
30-39 56 23.5 species was the most commonly isolated organisms
Age group
40-49 14 5.9 in 35 (33%) cases, followed by streptococcus
50-59 6 2.5
species 18 (17%), Neisseria species 13 (12.3%) and
60-69 2 0.8
70-79 1 0.4 a few staphylococcus species. The isolated bacteria
TOTAL 238 100 were most frequently sensitive to 3rd / 4th Generation
Cephalosporins and Amoxicillin/clavulanic acid.
The common types of tonsillitis noted were Some organisms were multi drug resistant, being
acute parenchymatous tonsillitis, acute follicular sensitive only to piperacillin, ceftriaxone, cefotaxime
tonsillitis and acute pharyngotonsillitis. Of the and meropenem. Antimicrobials were changed after
total, 7 (2.9%) patients had self-medicated prior to the culture and sensitivity test in 25 patients. Of these
the hospital visit. About 96% of the total number patients 12 patients were on parenteral antibiotics.
were prescribed by generic name. The median No pattern was noticed with regard to the change in
number of drugs prescribed was four (range 1-7). antimicrobial prescription however, oral Cefuroxime
A total of 925 medications were prescribed to was the most frequently added antimicrobial agent
238 patients with acute tonsillitis. 209 (88%) of based on the sensitivity report.
the prescriptions contained antimicrobial agents.
DISCUSSION
Antimicrobials (265) were the most commonly
prescribed group of drugs followed by analgesics The present study highlights the current trends in
(187) and antipyretics (138), as shown in Figure 1. antimicrobial prescriptions in the management
The prevalence and indicators of antimicrobials of acute tonsillitis at the outpatient department
used in the treatment of acute tonsillitis are shown of Otorhinolaryngology. A slightly higher male
in Table II. preponderance was noticed, in line with previous

An Acad Bras Cienc (2014) 86 (1)

454 LISHA J. JOHN, MEENU CHERIAN, JAYADEVAN SREEDHARAN and TAMBI CHERIAN

Figure 1 - Commonly prescribed drug classes in acute tonsillitis.

TABLE II
Prevalence and indicators of antimicrobial use.

Prevalence of Antimicrobial use No. (%)

Overall drug use (n = 238)
Average number of drugs per prescription 4
Percentage of drugs prescribed by generic name 96%
Percentage of prescriptions with injections 109 (45.7%)
Percentage of drugs prescribed from essential drug list 60%
Antimicrobial use
Total number of prescriptions with antimicrobials 209
Total number of antimicrobials prescribed 264
Number of antimicrobials by parenteral route 109
Average number of antimicrobials 1
Number of prescriptions with:
Antibacterial drugs 209
Single antibacterial agent 165
Multiple antibacterial agents
• Two drug combination 34
• Three drug combination 10

reports on the infections of the ear, nose and throat
(Ain et al. 2010, Pradhan and Jauhari 2007, Khan
et al. 2011). It was found that a majority of the patients
were in the age group of 20-29 years and the lowest
percentages were of the geriatric group. A similar
finding was reported by other studies from India
(Khan et al. 2011) and Thailand (Issarachaikul
and Suankratay 2013). This finding could be
explained due to the study’s setting being at the
ENT department, where one expects most patients
to be adults, whereas pediatric cases seen at ENT
department are referred to pediatricians.

An Acad Bras Cienc (2014) 86 (1)

 ANTIMICROBIALS IN ACUTE TONSILLITIS 455

TABLE III
Pattern of monotherapy and combination therapy in acute tonsillitis.

Antimicrobial drug class Individual antimicrobial Monotherapy Combination therapy Overall utilization
Penicillin Amoxicillin/Clavulanic acid 60 12 72
Cephalosporins Cefpodoxime 19 6 25
Cefidinir 18 5 23
Ceftriaxone 13 27 40
Cefuroxime 13 5 18
Cefexime 1 - 1
Macrolides Azithromycin 22 5 27
Clarithromycin 4 6 10
Clindamycin 5 - 5
Fluroquinolones Ciprofloxacin 4 - 4
Levofloxacin 1 1 2
Nitroimidazoles Metronidazole 1 34 35
Tinidazole - 3 3

The most commonly prescribed categories
of anti-bacterials were found to be from β-lactam
antimicrobials (Penicillin and Cephalosporins).
This finding was in par with several other studies
conducted by Ain et al. (2010), Khan et al.
(2011), Senok et al. (2009), Higashi (2009) and
Issarachaikul and Suankratay (2013).
Among the individual drugs, amoxicillin-
clavulanate followed by ceftriazone were the widely
utilized drugs in the present study, similar to a previous
report from India, but the common cephalosporin
prescribed in the latter study was cefopodoxime
(Ain et al. 2010). This finding contradicts (Senok et
al. (2009), Khan et al. (2011), Das et al. (2005) and
Rehan (2003), wherein the preferred antimicrobial
agents were amoxicillin, cefixime and ciprofloxacin
respectively. Reports from Japan documented
cefcapene, a third generation cephalosporin as the
most commonly prescribed antibiotic, followed
by clarithromycin (Higashi 2009). The reason
for prescribing amoxicillin/clavulanate and third
generation Cephalosporins could be due to the
preponderant mixed group of infections and increase
in antibiotic resistance, which encourages physicians
to choose a broader spectrum antibiotic.
The median number of drugs per prescription
was one, whereas Ain et al. (2010), Das et al. (2005)
and Rehan (2003) documented that the average
number of drugs per prescription was as high as
three drugs. The average number of drugs is an
important indicator to assess rational practice in
drug prescribing. The mean number of drugs per
prescription should be as low as possible to avoid
increased risk of drug interactions, adverse drug
effects, development of bacterial resistance, poor
patient compliance and increased treatment related
costs. This finding in the present study indicates the
practice of rationalization in prescribing drugs, to
minimize the total number of drugs prescribed.
The culture of prescriptions contained antimicrobials
in the present study and the culture and sensitivity
reports on throat swab were useful tools in assisting
clinicians in selecting the most appropriate
antimicrobial agents in individual patients. In a
study from Nepal 95.9% of prescriptions contained
antimicrobials in the treatment of acute tonsillitis
(Rehan 2003). In a publication from Thailand,
more than 80% of the prescriptions for upper
respiratory tract infections contained antimicrobials
(Issarachaikul and Suankratay 2013).
About 96% of the drugs in this study were
prescribed using generic names indicating a
rational practice of drug prescribing. Prescribing
by generic names reduce overall expenditure

An Acad Bras Cienc (2014) 86 (1)

456 LISHA J. JOHN, MEENU CHERIAN, JAYADEVAN SREEDHARAN and TAMBI CHERIAN
on drugs, especially on newer antibiotics, and
promote rational use of drugs. Prescribing by
trade name benefits drug promotional activities of
pharmaceutical companies, and undermines the
objectives of the essential drug concept.
One of the noteworthy findings was that a
significant proportion (41%) of the antimicrobial
were prescribed by parenteral route unlike earlier
studies where parenteral route was used only in
16% of the patients (Ain et al. 2010). The probable
reason for this finding was due to the acute
presentation of the symptoms in a majority of the
patients necessitating parenteral antibiotics.
The most commonly used antimicrobial fixed
dose drug combination (FDC) was Amoxicillin/
Clavulanic acid about 30%. Amoxicillin/Clavulanic
acid prescribed in this study is among the rational
FDC recommended by World Health Organization
(WHO 2013) in the management of upper
respiratory tract infections. Rehan (2003) reported
only 16.5% utilization of antimicrobial fixed drug
combination and the most common being Ampicillin
with cloxacillin. Khan et al. (2011) documented the
frequently used FDC in their study as Cefixime+
Clavulanic acid (9.7%) followed by Amoxicillin/
Clavulanic acid (9.5%).
Culture and sensitivity test of the throat swab was
carried out in 44.5% of the patients as other patients
were already on antimicrobials. Alpha hemolytic
streptococci species was the most commonly isolated
bacterial organisms in 33% of the cases which is one
of the commensal in the throat. This finding needs
to be further investigated to elucidate the role of
commensals in the pathogenesis of acute tonsillitis.
However, most of the isolated bacterial organisms
were sensitive to 3rd /4th Generation Cephalosporins
and Amoxicillin/clavulanic acid. A trend towards
multi drug resistance was also noted which needs to
be further explored.
The strength of the study is that it highlighted
several rational prescribing practices and newer
trends in the administration of antimicrobial
An Acad Bras Cienc (2014) 86 (1)
agents. The limitation of the study included non-
generalizability of the study findings as the study was
carried out at a single center; hence the results cannot
be generalized to the whole region. Considering the
findings of this study, treatment guidelines based
on the current sensitivity pattern for tonsillitis may
be developed to optimize the use of antimicrobial
agents and provide cost effective treatment.
Pharmacoeconomic studies can be undertaken to
establish cost effective treatment strategies
CONCLUSION
Beta lactam antimicrobials were the most commonly
prescribed antimicrobials. Injection was a widely
used route of administration of antimicrobials.
The majority of the patients received a single
antimicrobial. The majority of the medications were
prescribed in generic names encouraging rational
use of drugs. The culture and sensitivity tests
were performed in most of the cases to identify
the organism and to prescribe the appropriate
antimicrobials indicating a rational practice.
RESUMO
Fundamento: As doenças do ouvido, nariz e garganta
(ENT) estão associadas a comprometimento significativo
da vida diária e uma das principais causas de afastamento
do trabalho. Objetivo: O estudo teve como objetivo deter­
minar o padrão de prescrição de antimicrobianos em
pacientes com amigdalite aguda. Materiais e Métodos:
Foi realizado um estudo transversal com todos os
pacientes atendidos no Setor de Otorrinolaringologia e que
apresentavam amigdalite aguda. Os dados foram extraídos
dos prontuários médicos, utilizando uma pró-forma.
A análise estatística foi realizada utilizando SPSS.19.
Resultados: Total de 238 pacientes incluídos (homens 138;
mulheres 100). Cerca de 96 % do total de medicamentos
foram prescritos pelo nome genérico. O número médio
de medicamentos prescritos foi de quatro (intervalo 1-7).
Oitenta e oito por cento das prescrições continham
antimicrobianos, (78,5%), analgésicos e (57,9%) antipi­
réticos (57,9%). Amoxicilina / ácido clavulânico (24,8%)
 ANTIMICROBIALS IN ACUTE TONSILLITIS
e ceftriaxona (12,2%) foram os antimicrobianos mais
comumente prescritos. A via parenteral foi preferida
em 41,6 %. Cerca de 23,7% dos pacientes tratados com
Amoxicilina / Clavulanato receberam a droga por via
intravenosa. Testes de cultura e de sensibilidade foram
realizados em 106 (44,5%) dos casos. Os antimicrobianos
foram alterados / adicionados após a cultura e teste de
sensibilidade realizados em 25 pacientes. Conclusão:
Os achados destacam as práticas racionais na prescrição
de medicamentos. Diretrizes terapêuticas com base no
padrão de sensibilidade atual otimizam o uso de agentes
antimicrobianos.
Palavras-chave: utilização de drogas, utilização antimi­
crobiana, amidalite aguda, parenteral.
REFERENCES
AIN MR, SHAHZAD N, AQIL M, ALAM MS and KHANAM R.
2010. Drug utilization pattern of antibacterials used in ear,
nose and throat outpatient and inpatient departments of a
university hospital at New Delhi, India. J Pharm Bioall
Sci 2: 8-12.
AL KHAJA KA, SEQUEIRA RP, DAMANHORI AH, ISMAEEL AY
and HANDU SS. 2008. Antimicrobial prescribing trends in
primary care: implications for health policy in Bahrain.
Pharmacoepidemiol Drug Saf 7: 389-396.
ARROLL B. 2005. Antibiotics for upper respiratory tract
infections: An overview of Cochrane reviews. Respiratory
Medicine 99: 255-261.
BRINK AJ, COTTON MF, FELDMAN C, GEFFEN L, HENDSON
W, HOCKMAN MH, MAARTENS G, MADHI SA, MUTUA-
MPUNGU M and SWINGLER GH. 2004. Guideline for the
management of upper respiratory tract infections. S Afr
Med J 94(6- 2): 475-483.
DAS BP, SETHI A, RAUNIAR GP and SHARMA SK. 2005.
Antimicrobial utilization pattern in outpatient services of
ENT department of tertiary care hospital of Eastern Nepal.
Kathmandu Univ Med J 3: 370-375.
DASARAJU PV and LIU C. 1996. Infections of the Respiratory
System. In Medical Microbiology. 4th ed., Baron S, Ed.
Galveston (TX): University of Texas Medical Branch,
Galveston, Chapter 93. Available from: http://www.ncbi.
nlm.nih.gov/books/NBK8142/
EINARSON T. 2008. Pharmcoepidemiology. In: Parthasarathi
G, Hansen KN and Nahata MC (Eds), A Text book of Clinical
Pharmacy Practice essential concepts and skills. 1st ed.,
Hyderabad: Universities Press (India) Limited, p. 405-423.
EL-GILANY AH. 2000. Acute respiratory infections in primary
health care centres in northern Saudi Arabia. East Mediterr
Health J 6(5-6): 955-960.
GAASH B. 2008. Irrational Use of Antibiotics. Indian J
Practising Doctor 5(1): 3-4.
457
GRACE NN and BUSSMANN RW. 2006. Traditional management
of ear, nose and throat (ENT) diseases in Central Kenya. J
Ethnobiol Ethnomed 2: 54.
HIGASHI T and FUKUHARA S. 2009. Antibiotic prescriptions for
upper respiratory tract infection in Japan. Inter Med 48: 136.
ISSARACHAIKUL R and SUANKRATAY C. 2013. Antibiotic
prescription for adults with upper respiratory tract
infection and acute bronchitis at King Chulalongkorn
Memorial Hospital, Thailand. Asian Biomedicine 7(1):
15-20.
JAIN N, LODHA R and KABRA SK. 2001. Upper respiratory tract
infections. Indian J Pediatr 68:1135-1138.
KHAN FA, NIZAMUDDIN S and SALMAN MT. 2011. Drug
Utilization Patterns of Antimicrobial agents in the
Outpatient department of ENT in a tertiary care teaching
hospital of North India. JAPHR 1(2): 22-30.
LEBLEBICIOGLU H, CANBAZ S, PEKSEN Y and GUNAYDIN M.
2002. Physicians’ antibiotic prescribing habits for upper
respiratory tract infections in Turkey. J Chemother 14:
181-184.
LINDER JA. 2008. Evaluation and management of adult
pharyngitis. Compr Ther 34(3-4): 196-203.
MCCAIG LF, BESSER RE and HUGHES JM. 2002. Trends
in antimicrobial prescribing rates for children and
adolescents. JAMA 287: 3096-3102.
NAGHIPOUR M, HART CA and CUEVAS LE. 2007. Burden of
acute respiratory infections in a family cohort in Iran.
Epidemiol Infect 135(8): 1384-1388.
PICHICHERO ME. 2006. Pathogen shifts and changing cure
rates for otitis media and tonsillopharyngitis. Clin Pediatr
(Phila) 45(6): 493-502.
PRADHAN S and JAUHARI AC. 2007. A study of antibiotics
used in adult respiratory disorders in Kathmandu and
Bhaktapur. Nepal Med Coll J 9: 120-124
REHAN HS. 2003. Pattern of drug utilization in acute tonsillitis
in a teaching hospital in Nepal. Indian J Otolaryngol Head
Neck Surg 55(3):176-179.
SENOK AC, ISMAEEL AY, AL-QASHAR FA and AGAB WA.
2009. Pattern of upper respiratory tract infections and
physicians’ antibiotic prescribing practices in Bahrain.
Med Princ Pract 18: 170-174.
SRISHYLA MV, KRISHNAMURTHY M, NAGARANI MA, CLARE
SM, ANDRADE C and VENKATARAMAN BV. 1994.
Prescription audit in an Indian hospital setting using the
DDD (Defined Daily Dose) concept. Indian J Pharmacol
26: 23-28.
WHO - WORLD HEALTH ORGANIZATION. 2004. Chronic
suppurative otitis media: Burden of illness and
management options. Geneva, Switzerland: World Health
Organization. Available at: http://www.who.int/pbd/
deafness/activities/hearing_care/otitis_media.pdf
WHO - WORLD HEALTH ORGANIZATION. 2013. The 18th WHO
Model List of Essential Medicines. Geneva: World
Health Organization. Available at: http://www.who.int/
medicines/EMP_Website_notice_EML_July2013.pdf
An Acad Bras Cienc (2014) 86 (1)